Pertussis: Clinical Disease, Diagnosis, Treatment,

Epidemiology and Prevention2011

James D. Cherry, MD, MSc

Division of Infectious DiseasesMattel Children’s Hospital UCLA

Conflict of Interest Declaration

“I have the following financial relationships with the manufacturers(s) of pertussis vaccines:”

Speaker in programs supported by: Sanofipasteur and GSK

Consultant for: Sanofipasteur and GSK

“My plan is to give what I hope is a balanced presentation using the best available evidence to support my conclusions and recommendationsI do intend to discuss an unapproved use of commercial products in my presentation”.

A Bit of History

Whooping Cough:A Summary of its Peculiar Features-1940*

• Lacks an ancient history• The cough in the spasmodic stage is distinctive

though we don’t know why• It kills more girl babies than boys• There is no fever during the spasmodic stage,nor

are there any physical findings

*from Bacillary and Rickettsial Infections,Acute and Chronic a Textbook(Black Death to White Plague) by William H.Holmes,Professor of Medicine,Northwestern University Medical School

Pertussis Facts2011

• DTaP vaccines are less reactogenic than DTP vaccines,however they are less efficacious

• Of all our routine vaccines (except influenza) pertussis vaccines are the least effective

• B.pertussis infections are common in all age groups and this is not new

• Most adolescent and adult cases are not diagnosed as pertussis• Young infants get pertussis from adolescent and adult family

members• The potential severity of pertussis in young infants is often not

recognized by health care providers• The Dx of severe pertussis in young infants is often not made

Review

1) Clinical characteristics2) Epidemiology3) Dx and Rx4) Prevention of pertussis by

immunization5) Why vaccines fail

Clinical

Major Manifestations of Typical Pertussis

Three-stage illness (catarrhal, paroxysmal and convalescent) that lasts 4-12 weeks

Specific manifestationsparoxysmal coughlack of feverno systemic illnesscoryza; no pharyngitisposttussive vomitingposttussive whoopabsolute lymphocytosis

April 1991-February 1992

Total Days of Cough No. % Cumulative %1-7 11 4.5 4.48-14 28 11.3 15.815-21 24 9.7 25.522-28 54 21.9 47.4>28 130 52.6 100.0

Source: Heininger et al. Pediatr Infect Dis J 1993; 12: 504-9

Total Duration of Cough in 247 German Children with B. pertussis

Infections

Young Infants

Pertussis in Young Infants• Initially infant looks deceptively

well;coryza,sneezing,clearing throat,no fever,mild cough

• Paroxysmal stage:gagging,gasping,eye bulging,bradycardia,cyanosis,vomiting

• Leukocytosis with lymphocytosis• Apneic episodes• Seizures• Respiratory distress• Pneumonia• Adenovirus or RSV coinfection can confuse

picture

Pathology and Pathogenesis of Fatal Bordetella pertussis Infection in

Infants*

Christopher D. Paddock, Gary N. Sanden, James D. Cherry,et al

*CID 2008;47:328-338

Source of Pertussis in Infants

CDC Study –Infant Pertussis: Who Was the Source?

• 774 infant cases from 4 states

• 264 cases had source identified

• Sources:

Bisgard, K. PIDJ. 2004;23:985-9.

Mother 32%

Father 15%Sibling 20%

Grandparent 8%

Other 25%

Age of Pertussis Source* for Infants

*219 source-persons with known age

0

10

20

30

40

50

60

0-4 5-9 10-19 20+

Age of Source (Years)

% o

f Inf

ant C

ases

Bisgard, K. PIDJ. 2004;23:985-9.

Transmission of Pertussis to Young Infants

91≤ 6 month olds cases; source identified in 44 (48%).

Wendelboe et al PIDJ 2007;26:293-299

mothers 41%

fathers 20%

siblings 18%

aunt/uncle 11%

friend/cousin 11%

grandparent 7%

part-time caretaker 2%

* There were multiple source patients in some instances

Transmission of Pertussis to Young Infants

Age of 49 source patients

Wendelboe et al PIDJ 2007;26:293-299

Age in Years Percent

< 13 14%

13-18 16%

19-39 61%

40-64 8%

Prospective Multinational Study of Pertussis Infection in Hospitalized

Infants and Their Household ContactsKowalzik et al. PIDJ 2007;26:238-242

99 PICU Infants30 household contacts identified

Mother 50%Another adult 20%Sibling 17%Father 10%Another child 3%

Adolescents and Adults

Pertussis Pete*1. Peter G. boarded with his sister in Harlem.2. Two nieces and one nephew contracted whooping

cough. Peter began to cough a few weeks later.3. Beginning of March Peter visited another sister in

Brooklyn and 8 days later her children developed pertussis.

4. Peter went to live with brother; a week later the brother’s child developed pertussis.

5. Peter moved to cousin’s house and shortly thereafter neighbor’s child developed pertussis.

6. April 20th Peter sailed for Italy having enlisted in the army.

*Luttinger P. AJDC. 1916;12:290.

Pertussis in AdultsConclusions

1. Adult pertussis occurs more frequently than generally assumed.

2. Second attacks are more frequent than commonly believed.

3. Illness starts with insidious cough 1-3 weeks after exposure, lasts 5-6 weeks or longer, worse at night, gagging and choking common, and thick, white, tenacious phlegm is raised.

4. Blood count not characteristic.

Mannerstedt G, J. Pediatrics. 1934;5:596

Grandmothers Cough*Faroe Islands 1914-15

• It is worthy of note that many of the substantiated cases of whooping cough were second attacks so called “grandmothers whooping cough”; however, these were always light and shorter in duration than the first attacks.

*Madsen T. Boston M&S J. 1925;192:50.

Adult Pertussis in Vaccine Efficacy Trials

Gothenburg – Seven adult primary casesStockholm I – Four of 59 primary cases

were adultsII – Seven of 329 primary cases

were adultsMainz – 18 of 121 primary cases

were adultsErlangen – In 60 families an adult was the

primary case in 29 (48%) instances.

Seventyone Year Old Man (MD) with Pertussis

• Age 5 had pertussis;20 yrs ago wife had pertussis• 7/5/09 Exposed on airplane• 7/15/09 Onset of cough illness• 7/18/09 Sweating episode• 7/29/09 First whoop;Rx azithromycin• 8/3/09 Internist Dx “cough variant asthma”;decided to rule

out insulinoma;Rx predisone• 8/7/09 ENT Dx Wegener’s granulomatosis;CT head and

neck• 8/14/09 PCR positive• Aug-Oct coughing continued without improvement • Nov relapse of cough during a cold

Sweating Episodes

• ”I noticed that I felt faint and was sweating profusely”

• “My wife noticed that I had become drenched with sweat and that I looked gray”

• “After about 20 minutes, the sensation of light-headedness and the diaphoresis abated”

• “My internist also decided to rule out insulinoma as a cause of the episodes of light-headedness and diaphoresis”

SYMPTOMS OF PERTUSSIS IN 664 ADOLESCENTS AND ADULTS*

Characteristic PercentParoxysms 99Posttussive apnea 87Posttussive vomiting 65Whoop 69Sweating episode 32

* De Serres et al. JID 2000; 187: 174-9

COMPLICATIONS OF PERTUSSIS IN 664 ADOLESCENTS AND ADULTS*

Characteristic PercentSinusitis 13Otitis media 4Urinary incontinence 4Pneumonia 4Weight loss 3Rib Fracture 2Fainting 2*De Serres et al. JID 2000; 187: 174-9

An Epidemic of Pertussis Among Elderly People in a Religious Institution in the

NetherlandsEur J Clin Microbiol Infect Dis 1999; 18:242-247

Residents and personnel 99

Attack rate 49%

Death rate in residents 5% (4/75) (intracranial bleeding)

CLINICAL DIAGNOSES ASSIGNED BY THE PRIMARY CARE PROVIDERS AND ANTIBIOTIC THERAPY IN STUDENTS WITH COUGH

≥ 6 DAYS (Mink et al.CID.1992;14:464-471)Subjects with B. pertussis infection

Subjects without B. pertussis infection

(n = 31) (n = 84) p value*Diagnosis

URI 39% 33% 0.68Bronchitis 48% 64% 0.14Otitis/Sinusitis/Pharyngitis 0% 10% 0.11Pertussis 0% 1% 0.99Other 16% 8% 0.30

Antibiotics taken for illness prior to clinic visit

23% 14% 0.26

Antibiotics prescribed at the ti me of clinic visit

39% 64% 0.02

Erythromycin prescribed at the time of clinic visit

35% 52% 0.14

*Fisher’s Exact Test

CLINICAL CHARACTERISTICS OF COUGH IN STUDENTS WITH COUGH FOR ≥ 6 DAYS (Mink

et al.CID.1992;14:464-471)

Characteristic of Cough34 Students with B. pertussis Infection

96 Student without B. pertussisInfection

Median duration prior to study 21 days 14 days*

Frequency ≥ 1 episode/hour 94% 89%

Quality Staccato or paroxysmal 90% 82%

Productive with each episode 3% 21%†

Severity severe ‡ 40% 35%

* p = 0.92

† p – 0.02

‡ Definition: required interruption of all activities during episode

Clues in the Clinical Dx of Pertussis in Older Children,Adolescents and

Adults • Lack of fever• Lack of a truly productive cough• WBC,ESR and CRP normal• Feeling of a choking sensation• Cough worse at night; need to sleep sitting up• Sweating episodes• Normal between coughing episodes

Treatment

ChildrenErythromycin† = 40-50 mg/kg/day for 14 days administered

every 6 hours (maximum dose = 2 gms/day)Azithromycin = 10 mg/kg on day 1 and 5 mg/kg on days 2-5 as

a single dose/day (maximum dose = 500 mg on day 1 and 250 mg on days 2-5)

Clarithromycin = 15-20 mg/kg in 2 divided doses for 7 days (maximum dose = 1gm/day)

Trimethoprim-sulfamethoxazole = 8-12 mg of trimethoprim, 40-60 mg of sulfamethoxazole /day in 2 doses for 14 days (maximum dose = 320 mg of trimethoprim)

* Prophylactic dose is the same as the treatment dose† Recent data suggest that a 7 day treatment course is effective

ANTIMICROBIAL AGENTS FOR THE TREATMENT AND PREVENTION* OF

PERTUSSIS

AdultsAzithromycin = 500 mg on day 1 and 250 mg on

days 2-5 as a single dose/dayClarithromycin = 1 gm/day in 2 divided doses for 7

daysTrimethoprim-sulfamethoxazole = 320 mg of

trimethoprim, 1.6 gm of sulfamethoxazole/day in 2 doses for 14 days

* Prophylactic dose is the same as the treatment dose

ANTIMICROBIAL AGENTS FOR THE TREATMENT AND PREVENTION* OF

PERTUSSIS

Prophylaxis

Laboratory Diagnosis of B.

pertussis Infection

Culture

The main reasons for failure to isolate B. pertussis from correctly collected and transported specimens are:

1). Bacterial and fungal contamination

2). Lack of fresh media

3). Specimen collected too late in illness

PCR on NP Secretions

1). More sensitive than culture

2). With use of multiple primers can identify and separate other Bordetella sp

3). False positives are a problem

4). Delay in specimen collection is main reason for negative PCR

Serologic Diagnosis of B. pertussis Infection

When Pertussis Tests are Likely to be Positive in Infected People

Epidemiology

The Epidemiology of Reported Pertussis is Different from the Epidemiology of B. pertussis

Infection

Pertussis Epidemiology 1) In prevaccine era, pertussis was a universally present disease with

cyclic peaks every 2 to 5 years2) In the prevaccine era > 93% of reported cases occurred in children

< 10 years of age3) In the 1970s 50% of cases were reported in infants4) Recently about 65% of reported cases are in persons > 10 years of

age5) Immunization changed the rate of reported pertussis in the US

from 157 per 100,000, in the prevaccine era, to < 1 per 100,000 in the 1970s

6) Since 1984 there has been a modest increase in reported pertussis (from 1 to 8 cases per 100,000)

7) In the vaccine era the cyclic peaks of reported pertussis still occur at 2 to 5 year intervals

Possible Reasons for the Resurgence of Reported Pertussis

1) Genetic changes in B. pertussis2) Lessened potency of pertussis vaccines3) Waning of vaccine-induced immunity4) Greater awareness of pertussis5) The general availability of better

laboratory tests

Reported Pertussis

In spite of the fact that reported pertussis is only the “tip of the iceberg,” it is clear that cyclic disease pattern occurs and that this pattern has continued in the vaccine era.

0100200300400500600700800900

1950 1960 1970 1980 1990 2000

Cas

es (t

hous

ands

) Vaccine Licensed

Measles – United States, 1950-2002*

*2002 provisional data

Epidemiology of B. pertussisInfections

Issues1. Percentage of prolonged cough illnesses in

adolescents and adults due to B. pertussisinfections

2. Rate of B. pertussis infections in adolescents and adults

3. Rate of B. pertussis cough illnesses in adolescents and adults

Percentage of Prolonged Cough Illnesses in Adolescents and Adults Due to B. pertussis*

InfectionsAuthor Location Year Percent

Mink et al. Los Angeles 86-89 13%

Wright et al. Nashville 92-94 16%Nennig et al. San Francisco 94-95 12%

Strebel et al. Minneapolis/St. Paul 95-96 13%Birbeback et al. Denmark 95-97 17%Vincent et al. Korea 97-98 7%Dalby et al. Denmark 06-08 ~10%

* Significant IgA or IgG antibody titer rise or high titer to PT, or culture or PCR positive

Rate of B. pertussis Infection in Adolescents and Adults

Author Location Year Annual Rate

Deville et al.* Los Angeles, CA 84-89 6%

Cromer et al.* Columbus, OH 85-90 ~1%

Hodder et al.* Cleveland, OH 89-92 3%

Wright et al.* Nashville, TN 92-94 2.2%

Ward et al.* Eight US cities 97-99 1.3%

de Melker et al. † Netherlands 95-96 6.6%

* Infections were determined by the demonstration of a significant serum antibody titer rise to PT in successive serum samples

† Infections were determined by demonstration of PT values above their cut off limits

Rate of B. pertussis Cough Illnesses in Adolescents and Adults

Author Location Year Rate

Strebel et al. Minneapolis/St Paul 95-96 0.5%

Ward et al. Eight Centers, USA 97-99 0.37%

Hodder et al. Cleveland 89-92 1.5%

Summary 2011• B. pertussis infections in adolescents and adults are very

common and endemic in the present vaccine era• Data from Germany in the early 1990’s when few

children were being immunized and pertussis was epidemic, as well as early observations in the U.S., suggest that infections in adolescents and adults were also common and endemic in the prevaccine era

• Rates of reported pertussis are 40 to 160-fold less common than actual illness rates

• Asymptomatic infections are 4 to 22 times more common that symptomatic infections

• Today symptomatic adolescents and adults are the major source of infection in unvaccinated children

Pertussis Vaccines

Pertussis Vaccines

~1945 DTwP vaccines~1995 DTaP vaccines

PTPT,FHAPT,FHA,PRNPT,FHA,PRN,FIM

~2005 Tdap vaccinesPT,FHA,PRNPT,FHA,PRN,FIM 2/3

Virulence factors of Bordetella pertussis

TOXINS:• Pertussis toxin• Adenylate cyclase toxin• Dermonecrotic Toxin• Tracheal cytotoxin • Lipopolysaccharide

ADHESINS:• Filamentous hemagglutinin• Pertactin, BrkA, Vag8,

Tracheal colonization factor• Fimbriae (or pili)

Antibody To:

• PT-promotes neutrophil chemotaxis; prevents leukocytosis with lymphocytosis; prevents increased insulin secretion

• FHA-may block attachment• PRN-induces opsonic antibodies which facilitates

phagocytosis• FIM-agglutinates bacteria which blocks

attachment

Why Do Pertussis Vaccines Fail?

Possible Reasons Why DTP and DTaP Vaccines Fail

• Over expectation of efficacy due to case definition.• Over expectation of efficacy due to observer bias.• Other Bordetella sp are the cause of similar cough illnesses• Lack of initial potency.• Decay in antibody over time.• Incomplete antigen package.• Incorrect balance of antigens in the vaccine.• Linked-epitope suppression.• ELISA values measured are cross reacting antibodies• Genetic changes in B.pertussis

WHY ARE THERE MORE CASES IN PREVIOUS VACCINEES THAN IN

NONVACCINEES?Population 1000 90% immunized

VE= 70%Attack rate in nonvaccinees 70%

Vaccinees 900Number susceptible 270

Number of cases 189

Nonvaccinees 100

Number susceptible 100

Number of cases 70

VE = 70-21 = .70 x 100 = 70%70

Over Expectation of Efficacy due to Case Definition.

WHO Pertussis Case Definition(Geneva January 11, 1991)

≥21 days of paroxysmal cough and one or more of the following:• Positive culture of B. pertussis• Titer rise (ELISA) IgG or IgA to PT, FHA or Fim 2-3 • Household contact with culture confirmed case occurring 28

days of onset in trial child.

Vaccine Efficacies of Eight Acellular Pertussis Component Vaccines and Two Whole Cell

Pertussis Component VaccinesPercentEfficacy

Vaccine Components (95% CI)Amvax PT 31(-4-59)JNIH-7 PT -6(-49-24)JNIH-6 PT, FHA 43(15-61)SKB PT, FHA 42(33-51)SKB PT, FHA, PRN 71(60-78)Chiron-Biocine PT, FHA, PRN 71(61-79)Lederle/Takeda PT, FHA, PRN, 62(38-77)

FIM-2Connaught PT, FHA, PRN 78(73-82)(Canada) FIM-2,3Wyeth- Lederle Whole Cell 78(62-88)

Connaught Whole Cell 41(30-51)(USA) to 23(1-40)

Over Expectation of Efficacy Due to Observer Bias

Percent Vaccine Efficacy by Investigator Compliance Category Against Mild and Typical and

Typical Pertussis Attributable to B. pertussis*

Investigator Compliance Category

Mild and Typical Pertussis (95% CI)

Typical Pertussis (95% CI)

DTaP DTP DTaP DTP

High 40 (3-65) 73 (48-86) 69 (41-83) 90 (75-96)

Low 75 (53-87) 85 (68-93) 84 (64-93) 93 (80-98)

* Cherry et al., Pediatrics 1998; 102: 909-912

Decay of Antibody Over Time

PT FHA PRN FIM 2/3Postdose 3 90 74 36 268Predose 4 11 13 6 36Postdose 4 174 108 94 553Predose 5 10 8 9 35

Geometric Mean Values (EU/ml) Postdose 3, Predose 4, Postdose 4 and Predose 5 *

* Guerra. Pediatrics. 2009; 123:301-312

Other Bordetella sp are the Cause of Pertussis

“17% in California in 2010”

Genetic Changes in B.pertussis

Genetic Changes in B.pertussis-2010

• Vaccine pressure has resulted in changes in PT,PRN and FIM.

• Since DTP vaccines contain multiple antigens these genetic changes are unlikely to lead to vaccine failure.

• Since DTaP and Tdap vaccines contain fewer antigens it seems possible that genetic changes will lead to vaccine failure. Particularly with PT and PT/FHA vaccines.

• DTP vaccines generally have greater efficacy than DTaP and Tdap vaccines

• All vaccine efficacy has been inflated due to case definition and observer bias

• The main reason for vaccine failure is antibody decay, and perhaps incomplete antigen package, and incorrect antigen balance.

Summary

• Recognize that B. pertusiss is circulating in all age groups and therefore for herd immunity need to universally vaccinate all age groups at frequent intervals

• Develop new vaccines1. DTaP vaccines with multiple

additional components and minimal PT2. “live vaccines”3. DTP vaccines with detoxified LPS

Approach to the Problem

What Can You do?

• Dx and Rx pertussis.• Educate those who care for adults that

pertussis is common in adults, usually misdiagnosed and it can be prevented by Tdap.

• Promote cocooning around infants.• Fill in the gaps-7 to 9 year olds, DTaP or

Tdap; >64 year olds,Tdap.

Conclusions1) B pertussis infections in adolescents and adults are common and endemic.2) Immunity after infection or vaccination is not long lasting.3) The outcome of an infection depends upon the time since vaccination or a

previous infection.4) Endemic adolescent and adult disease is responsible for the cyclic pattern

in unvaccinated children.5) B pertussis circulation cannot be controlled by present immunization

programs.6) A universal program with adolescent and adult Tdap boosters would

decrease the circulation of B.pertussis in these age groups and might lead to the elimination of the organism from the population.

7) Since this is unlikely to occur in the near future the best strategy at present is universal adolescent immunization and vigorous cocooning.

Cherry JD. Pediatrics 2005;115:1422-1427.

Conclusions

Our number one priority today regarding vaccine preventable diseases should be to find a way to universally vaccinate adults as well as children. We need to find a method to see that all adults get the immunizations they need including protection against B. pertussis infection.